Selective Serotonin Reuptake Inhibitors (SSRI) constitute the class of medications that are currently most widely used for the treatment of depression and anxiety disorders, obsessive-compulsive disorder, phobias, social phobia and panic.
These drugs act on the serotonin transporter, a protein integrated with the membrane whose function is to transport the neurotransmitter—serotonin—from the synaptic spaces to the interior of the pre-synaptic neurons. Its inhibition by the SSRIs triggers an increase in the serotonin concentration in the synapses, resulting in greater availability of this neurotransmitter for binding with the serotonin receptors of the contiguous neurons, with the consequent propagation of the nerve impulse. Although the SSRIs extend the availability of serotonin in the synapses, this neurotransmitter is not specific for binding with the different existing serotonin receptors.
At the moment, seven families or populations of serotonin receptors are known, classified from 5-HT1 to 5-HT7 on the basis of their different structural and operating characteristics. Multiple subpopulations or subtypes (homologous types and conjugated variants) exist for each of these families. While some subtypes have been targeted by many studies allowing their characterization in structural and functional terms, the function of other subtypes have not yet been fully elucidated (Psychopharmacology—4th Generation—Serotonin Receptors, Subtypes and Ligands—Glennon et al, available at: http://www.acnp.org/g4/GN401000039/Ch039.html).
In addition to interacting with the serotonin transporter, serotonin interacts indistinctly with all the populations and the respective subpopulations of the serotonin receptors. If on the one hand the increase on the concentration of serotonin has a positive therapeutic effect that is appropriate for treating certain dysfunctions, on the other side this increase prompts the appearance of undesired side effects, probably resulting from the indiscriminate activation of non-specific receptors that are not related to the disorders being treated.
Several studies describe the importance of the 5-HT1A agonism, with the activation of these receptors being particularly relevant for the treatment of depression and anxiety disorders, phobias, panic impulsiveness, obsessive-compulsive disorder, among others. Some drugs have been developed, specifically targeting these receptors. This is the case of buspirone and tandospirone which, although serving as partial agonists, target only the 5-HT1A receptors, not presenting any significant affinity for other serotonin receptors.
Although these drugs target the 5-HT1A receptors whose activation is acknowledged as important in the treatment of these various disorders, they are not rated as first choice drugs, mainly because their effects in the treatment of depression and other associated disorders are significantly less than those presented by the SSRIs. Among the hypotheses presented to explain this behavior, or deficiency of activity, is the fact that they act as partial agonists with these receptors. In fact, the mechanism of action of buspirone occurs through the agonism of the pre-synaptic 5-HT1A receptors, while it acts together with the post-synaptic 5-HT1A receptors as a partial agonist (The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition, Chap. 25—Buspirone and Gepirone—edited by Alan F. Schatzberg and Charles B. Nemeroff).
Recent studies indicate that 5-HT1A and 5-HT2A receptors are particularly involved in disorders related to depression and anxiety. While the agonism of the 5-HT1A receptors seems to have a favorable therapeutic effect in the treatment these disorders, the antagonism of the 5-HT2A receptors seems to be responsible for triggering a similar effect. Thus, it is believed that the therapeutic effect arising from the agonism of the 5-HT1A receptors is partially neutralized should the substance promote in parallel the agonism of the 5-HT2A receptors, indicating the possible existence of a functional antagonism between the two receptors (Marek et al in Neuropsychopharmacology (2003) 28: 402-412; Celada et al in J. Psychiatry Neurosci. (2004) 29 (4): 252-265).
The long latency period between the start of the treatment and the appearance of the initial effects noted in patients being treated with the SSRIs, may be associated at least partially with the increased concentration of serotonin available to the 5-HT2A receptors. It is also suspected that the agonism of the 5-HT2A receptors is responsible for some of the side effects attributed to the SSRIs, including sexual dysfunction.
Recently, a drug under development drew fresh attention to the joint modulation of the 5-HT1A and 5-HT2A serotonin receptors, when its dual mechanism of action triggered promising effects in the treatment of female sexual dysfunctions. Although the mechanism of action of this drug has not yet been fully explained, the participation of these two receptors in female sexual functioning had already been addressed by Meston et al (Current Opinion in Urology (2001) 11: 603-609), who mentioned that there is evidence that the activation of the 5-HT2 receptors would hamper sexual functioning, while the stimulation of the 5-HT1A receptors would facilitate this, which might be the reason why the SSRIs produce side effects.
In view of the matters set forth above, the quest for drugs that could interact simultaneously with the 5-HT1A and 5-HT2A receptors may well offer better control or more effective treatment for several disorders, which could be accompanied by a briefer latency period for the appearance of the therapeutic effect and also a reduction, moderation or elimination of the side effects that are noted when the SSRIs are employed, being agents that, due to their mechanism of action, trigger and increase in the serotonin concentration that acts in a non-selective manner on all the serotonin receptors.
Several pharmacological properties are attributed to substances belonging to the quinazolinone class. More specifically, with regard to the alkyl-phenylpiperazine-4(3H)-quinazolinones, derivatives of this type were described in the state of the art presenting sedative, hypnotic, anti-hypertensive and anti-inflammatory properties.
U.S. Pat. No. 3,047,462 describes 4 (3H)-quinazolinones, in addition to other 4-quinazolines, which present anti-inflammatory properties.
U.S. Pat. No. 3,073,826 describes 3-pyrrolidylmethyl-4(3H)-quinazolinones, which present anti-inflammatory properties.
U.S. Pat. Nos. 3,086,910, 3,448,109 and 3,928,354 describe substituted 4 (3H)-quinazolinones, 2-methyl and 3-aryl, which are endowed with hypnotic, muscle relaxant and anti-spasmodic activities. The substances described in these documents present ample structural similarity with methaqualone and its derivatives, which are hypnotic agents whose sale was suspended due to their high potential for developing dependency and abuse.
U.S. Pat. No. 3,231,572 describes substituted 4 (3H) quinazolinones, 2-methyl or phenyl and substituted 3-alkyl-piperazinyl-phenyl that are useful as anti-inflammatory agents or sedative agents. The tests conducted with the compounds described in this document demonstrated that these substances are endowed with hypotensive and anti-histaminic properties, not presenting any sedative properties (Journal of Organic Chemistry (1969), 12: 936-938, Shin Hayao et al). U.S. Pat. No. 3,984,555 describes substituted aryl-piperazinyl-alkyl-4(3H) quinazolone derivatives that have hypotensive, anti-histaminic and analgesic properties. Most of the compounds synthesized in this document are di-substituted 4 (3H)-quinazolinones 6,7-methoxy, bound in position 2 of the quinazolinones by an alkyl chain of one, two or three carbon atoms with the piperazine-phenyl portion substituted by 2, 3 or 4 methyl, methoxy, chlorine or fluor. The authors affirm that these compounds are endowed with properties that are particularly useful in the treatment of hypertension.
U.S. Pat. No. 4,841,051 describes substituted 4 (3H)-quinazolinones ethyl-piperazine-phenyl-2-ethoxy that have an activity blocking the α1 receptors, being useful in the treatment of hypertension.
Compounds belonging to the quinazolinedione class were described in U.S. Pat. Nos. 3,274,194, 3,726,979, 4,335,127, 4,578,465 and 5,264,438.
U.S. Pat. No. 3,274,194 describes substituted 2,4 (1H,3H)-quinazolinediones-3-derivatives, which are useful as anti-inflammatory and sedative agents. This document describes pelanserin, a hypotensive agent that was subsequently discovered to be an antagonist of the 5-HT2 receptors without presenting affinity for the 5-HT1A receptors. The description that these compounds are serotonin antagonists is presented in U.S. Pat. No. 3,726,979.
U.S. Pat. No. 4,335,127 describes substituted 2,4-(1H,3H)quinazolinediones-3-alkyl-piperidine derivatives as compounds that are powerful serotonin antagonists. Among the compounds most studied described in this patent are ketanserin, altanserin and butanserin. All these compounds are endowed with high affinity for the 5-HT2A receptors, without presenting any affinity for the 5-HT1A receptors.
U.S. Pat. No. 4,578,465 describes substituted 2,4-(1H,3H)quinazolinediones-alkyl-methoxy-phenyl-piperazine compounds, with serotonin antagonist properties and able to block the alpha-adrenergic receptors.
U.S. Pat. No. 5,264,438 describes derivatives belonging to the 2,4 (1H,3H)-quinazolinedione family, which are endowed with serotonin antagonist properties, acting particularly as antagonists of the 5-HT2 receptors, in addition to presenting antagonist properties together with the α1-adrenergic receptors and agonists together with the dopaminergic receptors.
Other compounds presenting serotonin activity and the receptors involved, without belonging to the quinazolinone or quinazolinedione classes, were described in U.S. Pat. No. 3,717,634, GB 2.023.594 and 4.203.98.
U.S. Pat. No. 3,717,634 describes N-heteroaryl-cyclic-piperazinyl-alkyl compounds derived from 8-azaspyro[4,5]decane-7,8-dione, which are endowed with activity together with the 5-HT1A receptors, with the main representative being buspirone, an agent with anxiolytic properties. This substance acts as a partial agonist on the 5-HT1A receptors, not presenting interaction or affinity for the 5-HT2A receptors.
GB Patent 2.023.594 describes substituted 4-(3-trifluoro-methyl-thiophenyl)-piperazines-1-alkyl which may have substitutions binding to the alkyl group. The compounds described present activity with the central nervous system.
U.S. Pat. No. 4,203,986 describes substituted m-trifluoromethyl phenylpiperazines N-alkyl and/or cycloalkyl presenting activity with the central nervous system and the cardiovascular system, associated with sedative, tranquilizing and anti-tussive properties. Among the documents that describe compounds with selective affinity for the 5-HT1A and 5-HT2A receptors are U.S. Pat. Nos. 5,576,318, 6,586,435 and 6,281,218 that describe N-substituted benzimidazolones by substituted alkyl mono and di-phenylpiperazines, with these compounds presenting affinity for the 5-HT1A and 5-HT2A receptors, being useful for the treatment of central nervous system disorders, such as the treatment of depression, anxiety, neurodegenerative diseases and psychoses, for example, among others. The best compound known compound in this class of substances described in these documents is flibanserin, a drug whose clinical trials showed that it was not efficient for the treatment of depression and that is currently undergoing clinical trials for the treatment of hypoative sexual desire disorder and other female sexual dysfunctions.
Kleven et al (Journal of Pharmacology and Experimental Therapeutics (1997), 282: 747-759) describe other substances presenting affinities for the 5-HT1A and 5-HT2A/2C receptors and that may be useful in the treatment of anxiety and depression disorders. These substances, initially proposed in U.S. Pat. Nos. 4,797,489, 5,166,157, 5,565,455, 4,604,397 and 4,721,787, are at various phases of studies for the treatment of disorders related to the modulation of these receptors.
Although there are theories defending the possible clinical advantages of developing drugs directed towards the 5-HT1A and 5-HT2A receptors, the substances developed so far and presenting this activity profile have not yet demonstrated the clinical efficacy required for their approval by the regulatory authorities, in addition to demonstrating effects fall well below the effects obtained with the SSRIs.
Surprisingly, the current inventors synthesized a particular family of compounds of the substituted 4 (3H)-quinazolinones-alkyl-piperazine-phenyl type, whose representatives present a high affinity for the 5-HT1A and 5-HT2A receptors and thus may be useful in the treatment or cure of several disorders associated with these receptors.
So far, the 4 (3H)-quinazolinones similar to those now described demonstrated that they are endowed with anti-hypertensive and/or anti-histaminic properties, with no circumstantial evidence indicating that they might be useful for the treatment of disorders attributed to modulations of the serotonin system, more specifically acting on the 5-HT1A and 5-HT2A receptors.
Studies conducted with the compounds addressed by this invention demonstrated that they gather together the structural characteristics that are appropriate for binding with the 5-HT1A and 5-HT2A receptors, with these properties related to the adequate size of the alkyl chain for linking the 4 (3H)-quinazolinone portion with the phenylpiperazine portion, associated with the need for the presence of steering groups that are appropriate and correctly oriented in the phenyl portion of the phenylpiperazine to promote anchoring of the appropriate confirmation of these compounds to these receptors.
Thus, this invention addresses substituted 4 (3H)-quinazolinones-alkyl-piperazine-phenyl compounds that have an affinity for the 5-HT1A and 5-HT2A serotonin receptors, with these compounds being useful in the treatment of persons affected by disorders associated with these receptors, such as depression, anxiety, phobias, addictions, aggressiveness, impulsiveness, panic, eating, sleep and psychotic disorders and obsessive-compulsive disorder in addition to being able to act on the heat regulation mechanism, presenting neuroprotective properties and also able to act on or assist with the treatment of female sexual dysfunctions, which encompass hypoative sexual desire disorder, sexual aversion disorder, female sexual excitation disorder, and the loss, inhibition or absence of sexual desire.